U.S. Pat. No. 5,849,911 to Fässler et al. discloses a series of azapeptide HIV protease inhibitors (which includes atazanavir) which have the structure
wherein
R1 is lower alkoxycarbonyl,
R2 is secondary or tertiary lower alkyl or lower alkylthio-lower alkyl,
R3 is phenyl that is unsubstituted or substituted by one or more lower alkoxy radicals, or C4-C8 cycloalkyl,
R4 is phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl that is bonded by way of a ring carbon atom, has from 5 to 8 ring atoms, contains from 1 to 4 hetero atoms selected from nitrogen, oxygen, sulfur, sulfinyl (—SO—) and sulfonyl (—SO2—) and is unsubstituted or substituted by lower alkyl or by phenyl-lower alkyl,
R5, independently of R2, has one of the meanings mentioned for R2, and
R6, independently of R1, is lower alkoxycarbonyl, or a salt thereof, provided that at least one salt-forming group is present which includes various pharmaceutically acceptable acid addition salts thereof.
Several methods for preparing the azapeptides are provided including preparation of a compound where R1 and R6, and R2 and R5 are in each case two identical radicals, wherein a diamino compound of the structure
is condensed with an acid of the structure
or with a reactive acid derivative thereof, wherein R1′ and R2′ are as defined for R1 and R6, and for R2 and R5, respectively.
In forming atazanavir employing the above method the diamino compound (a) which will have the structure
is prepared by coupling the epoxide
with a hyrazinocarbamate
in the presence of isopropyl alcohol to form the protected diamine
which is treated with hydrochloric acid in the presence a solvent such as tetrahydro-furan to form the diamine (a)
The diamine is isolated and used in the next coupling step where it is reacted with an acid (b)
or a reactive ester thereof employing a coupling agent such as O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N1,N1-tetramethyluronium-tetrafluoro-borate (TPTU).
It has been found that the diamine free base is unstable and therefore undesirable for use in preparing the free base of atazanavir.
U.S. Pat. No. 6,087,383 to Singh et al. discloses the bisulfate salt of the azapeptide HIV protease inhibitor known as atazanavir which has the structure
(also referred to as atazanavir bisulfate or atazanavir sulfate).
Example 3 of Singh et al. describes the preparation of atazanavir bisulfate in the form of Type-II crystals which are a hydrated hygroscopic and crystalline form and Type-I crystals which appear to be an anhydrous/desolvated crystalline form.